Antibody targeting osteoclast-related protein Siglec-15

Abstract

To provide a method of detecting abnormal bone metabolism by using a gene strongly expressed in an osteoclast; a method of screening a compound having a therapeutic and/or preventive effect on abnormal bone metabolism; and a pharmaceutical composition for treating and/or preventing abnormal bone metabolism. Provision of a method of detecting abnormal bone metabolism by using the expression of human Siglec-15 gene as an index; a pharmaceutical composition containing an antibody which specifically recognizes human Siglec-15 and has an activity of inhibiting osteoclast formation; and the like.

The invention claimed is: 
     
       1. A method of treating abnormal bone metabolism comprising administering a pharmaceutical composition comprising a monoclonal antibody or an antigen binding fragment thereof to a subject in need thereof, wherein the monoclonal antibody or the antigen binding fragment of the monoclonal antibody directly binds one or more amino acid sequences selected from the group consisting of:
 (a) amino acid residues 21 to 328 of the amino acid sequence of SEQ ID NO: 2; 
 (b) amino acid residues 1 to 260 of the amino acid sequence of SEQ ID NO: 2; 
 (c) amino acid residues 21 to 260 of the amino acid sequence of SEQ ID NO: 2; 
 (d) amino acid residues 21 to 341 of the amino acid sequence of SEQ ID NO: 4; 
 (e) amino acid residues 1 to 258 of the amino acid sequence of SEQ ID NO: 4; and 
 (f) amino acid residues 21 to 258 of the amino acid sequence of SEQ ID NO: 4, 
 where (a)-(f) are in one or more polypeptides; 
 wherein the monoclonal antibody or the antigen binding fragment of the monoclonal antibody contains the same Complementarity Determining Regions (CDRs) as a monoclonal antibody produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FERM BP-10999) and hybridoma #41B1 (FERM BP-11000); 
 wherein said binding of said antibody or antigen binding fragment inhibits osteoclast formation and/or osteoclastic bone resorption; and 
 wherein the abnormal bone metabolism is characterized by insufficient bone growth, mass, or density. 
 
     
     
       2. The method of  claim 1 , wherein said antibody or antibody fragment inhibits osteoclast formation. 
     
     
       3. The method of  claim 1 , wherein said antibody or antibody fragment inhibits osteoclastic bone resorption. 
     
     
       4. The method according to  claim 1 , wherein the osteoclast formation is induced by TNF-α. 
     
     
       5. The method according to  claim 1 , wherein the antibody or the antigen binding fragment thereof, inhibits in vitro osteoclast formation at a concentration of 30 μ,g/ml or less, 3 μg/ml or less, 1 μg/ml or less, or from 63 ng/ to  1  μg/ml. 
     
     
       6. The method according to  claim 1 , wherein the antibody or the antigen binding fragment thereof inhibits in vitro osteoclastic bone resorption at a concentration of 3 μg/ml or less or from 0.3 μg/ml to 3 μg/ml. 
     
     
       7. The method according to  claim 1 , wherein the antibody or the antigen binding fragment thereof, inhibits the process of cell fusion of osteoclasts. 
     
     
       8. The method according to  claim 1 , wherein the abnormal bone metabolism is selected from the group consisting of osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy and osteogenesis imperfecta. 
     
     
       9. The method according to  claim 8 , wherein the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis caused by the use of a therapeutic agent selected from the group consisting of a steroid and an immunosuppressant, or osteoporosis accompanying, rheumatoid arthritis. 
     
     
       10. The method according to  claim 1 , wherein the antibody has at least the same binding activity as an antibody produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FIRM BP-10999), and hybridoma #41B1 (FERM BP-11000). 
     
     
       11. The method according to  claim 1 , wherein the antibody has the same cross-reactivity as an antibody produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FERM BP-10999), and hybridoma #41B1 (FERM BP-11000). 
     
     
       12. The method according to  claim 1 , wherein the antibody is produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FERM BP-10999) and hybridoma #41B1 (FERM BP-11000). 
     
     
       13. The method according to  claim 1 , wherein the antibody is a chimeric antibody. 
     
     
       14. The method according to  claim 1 , wherein the antibody is humanized. 
     
     
       15. The method according to  claim 1 , wherein the antibody is a human anti body. 
     
     
       16. The method according to  claim 1 , wherein the antigen binding fragment is selected from the group consisting of Fab, F(ab′)2, Fab′, scFv, and Fv. 
     
     
       17. The method of  claim 1 , wherein the antibody is an IgG antibody. 
     
     
       18. The method of  claim 1 , wherein the pharmaceutical composition further comprises at least one agent selected from the group consisting f bisphosphonate, active vitamin D 3  calcitonin, hormones, ipriffavone, vitamin K 2  (menatehenone), calcium, PTI (parathyroid hormone), nonsteroidal anti inflammatory agent, soluble TNF receptor, anti-TNF-a antibody or-an antigen binding fragment thereof, anti-PTHrP (parathyroid hormone-related protein) antibody or-an antigen binding fragment thereof, anti-IL-6receptor antibody or an antigen binding fragment thereof, anti-RANKL antibody or an antigen binding fragment thereof, and OCIF (osteoclastogenesis inhibitory factor). 
     
     
       19. The method according to  claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 
     
     
       20. The method of  claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, solubilizing agent, emulsifying agent, preservative or adjuvant. 
     
     
       21. The method of  claim 1 , wherein the pharmaceutical composition further comprises a substance for pharmaceutical use which is capable of changing or maintaining the pH, osmotic pressure, viscosity, transparency, color, isotonicity, aseptic condition, stability, solubility, release rate, absorption rate, or permeability. 
     
     
       22. The method of  claim 1 , wherein the pharmaceutical composition is parenterally or orally administered. 
     
     
       23. A method of treating abnormal bone metabolism comprising administering a pharmaceutical composition comprising a monoclonal antibody or an antigen binding fragment thereof to a subject in need thereof; wherein the monoclonal antibody or the antigen binding fragment of the monoclonal antibody is produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FERM BP-10999) and hybridoma #41B1 (FERM BP-11000); and
 wherein the abnormal bone metabolism is characterized by insufficient bone growth, mass, or density. 
 
     
     
       24. A method of treating abnormal bone metabolism comprising administering a pharmaceutical composition comprising a monoclonal antibody or an antigen binding fragment thereof to a subject in need thereof; wherein the monoclonal antibody or the antigen binding fragment of the monoclonal antibody directly binds one or more amino acid sequences encoded by a nucleotide sequence selected from the group consisting of:
 (a) the nucleotide sequence of SEQ ID NO: 19; 
 (b) the nucleotide sequence of SEQ ID NO: 43; 
 (c) the nucleotide sequence of SEQ ID NO: 1; and 
 (d) the nucleotide sequence of SEQ ID NO: 3, 
 where (a)-(d) are in one or more polypeptides; 
 wherein the monoclonal antibody or the antigen binding fragment of the monoclonal antibody contains the same Complementarity Determining Regions (CDRs) as a monoclonal antibody produced by a hybridoma selected from the group consisting of hybridoma #32A1 (FERM BP-10999) and hybridoma #41B1 (FERM BP-11000); 
 wherein said binding of said antibody or antigen binding fragment inhibits osteoclast formation and/or osteoclastic bone resorption; and 
 wherein the abnormal bone metabolism is characterized by insufficient bone growth, mass, or density. 
 
     
     
       25. The method of  claim 18 , wherein the hormone is estradiol. 
     
     
       26. The method according to  claim 14 , wherein the antibody is a humanized antibody of the antibody produced by hybridoma cell line #32A1 (FERM BP-10999) or hybridoma #41B1 (FERM BP-11000).